Chaperone-mediated autophagy: Molecular mechanisms and physiological relevance

Orenstein, Samantha J.; Cuervo, Ana María

doi:10.1016/j.semcdb.2010.02.005

Cited by 241 publications

(204 citation statements)

References 52 publications

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“…The substrates bind to the lysosomal protein LAMP-2A and are translocated across the lysosomal membrane for degradation. 16 Macroautophagy is the major type of autophagy and it is well conserved from yeast to mammals. Non-selective or bulk autophagy is induced by starvation to provide the cell with essential nutrients.…”

Section: Overview Of Autophagymentioning

confidence: 99%

The pathways of mitophagy for quality control and clearance of mitochondria

2012

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Selective autophagy of mitochondria, known as mitophagy, is an important mitochondrial quality control mechanism that eliminates damaged mitochondria. Mitophagy also mediates removal of mitochondria from developing erythrocytes, and contributes to maternal inheritance of mitochondrial DNA through the elimination of sperm-derived mitochondria. Recent studies have identified specific regulators of mitophagy that ensure selective sequestration of mitochondria as cargo. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the autophagic machinery to mitochondria, while mammalian Nix is required for degradation of erythrocyte mitochondria. The elimination of damaged mitochondria in mammals is mediated by a pathway comprised of PTEN-induced putative protein kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin. PINK1 and Parkin accumulate on damaged mitochondria, promote their segregation from the mitochondrial network, and target these organelles for autophagic degradation in a process that requires Parkin-dependent ubiquitination of mitochondrial proteins. Here we will review recent advances in our understanding of the different pathways of mitophagy. In addition, we will discuss the relevance of these pathways in neurons where defects in mitophagy have been implicated in neurodegeneration. Facts Mitophagy mediates clearance of damaged mitochondria, and is also involved in the removal of mitochondria from maturing erythrocytes and eliminating sperm-derived mitochondria after fertilization. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the core autophagic machinery to mitochondria for their selective removal. A pathway containing PTEN-induced putative protein kinase 1 (PINK1) and Parkin responds to loss of mitochondrial membrane potential by targeting damaged mitochondria for clearance. The PINK1/Parkin pathway is triggered when PINK1 is stabilized on the outer membrane of damaged mitochondria, where it facilitates recruitment of cytosolic Parkin. Damaged mitochondria are prevented from moving and fusing with the mitochondrial reticulum in preparation for their mitophagic clearance. Open QuestionsHow distinct are the mitophagy pathways triggered by different stimuli or conditions?To what extent does Parkin activate mitophagy by causing the degradation of mitochondrial surface proteins or hyperubiquitinating the mitochondrial surface? How do PINK1 and Parkin interact with one another and with substrates on the mitochondrial surface in causing mitophagy? In contrast to the remarkable conservation of the core autophagic machinery, why are mitophagy-specific genes so little conserved between yeast and mammals? How best should mitophagy be triggered by researchers probing physiologically relevant pathways?The mitochondrion is an important actor in the life of a eukaryotic cell, but, like all good actors, a mitochondrion needs to exit the stage at the right time. Mitophagy removes mitochondria once they have played their part. This artic...

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Section: Overview Of Autophagymentioning

confidence: 99%

The pathways of mitophagy for quality control and clearance of mitochondria

2012

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“…Increasing evidence demonstrates that malfunction of CMA plays a key role in the pathogenesis of severe human disorders [45][46][47]. Often, the mechanisms underlying the alterations of CMA in these pathologies involve perturbations in the functioning of the CMA translocation complex.…”

Section: How Do Alterations In Cma Contribute To Disease?mentioning

confidence: 99%

Chaperone-mediated autophagy: roles in disease and aging

2013

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This review focuses on chaperone-mediated autophagy (CMA), one of the proteolytic systems that contributes to degradation of intracellular proteins in lysosomes. CMA substrate proteins are selectively targeted to lysosomes and translocated into the lysosomal lumen through the coordinated action of chaperones located at both sides of the membrane and a dedicated protein translocation complex. The selectivity of CMA permits timed degradation of specific proteins with regulatory purposes supporting a modulatory role for CMA in enzymatic metabolic processes and subsets of the cellular transcriptional program. In addition, CMA contributes to cellular quality control through the removal of damaged or malfunctioning proteins. Here, we describe recent advances in the understanding of the molecular dynamics, regulation and physiology of CMA, and discuss the evidence in support of the contribution of CMA dysfunction to severe human disorders such as neurodegeneration and cancer.

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“…Chaperone-mediated autophagy (CMA) is a potential alternative route that may deliver antigen to the MHCII antigen presentation pathway. CMA describes the selective delivery of cytoplasmic peptides and proteins directly into the lumen of the lysosome (Orenstein and Cuervo, 2010;Li et al, 2011b). The CMA machinery, including heat shock cognate protein of 70 kDa (hsc70) that selects peptide substrates, and multimeric lysosomal-associated membrane protein 2A (LAMP-2A) complex, facilitates the entry of peptide into the lysosome (Orenstein and Cuervo, 2010;Li et al, 2011b).…”

Section: Autophagy In Mhc Class II Antigen Presentationmentioning

confidence: 99%

“…CMA describes the selective delivery of cytoplasmic peptides and proteins directly into the lumen of the lysosome (Orenstein and Cuervo, 2010;Li et al, 2011b). The CMA machinery, including heat shock cognate protein of 70 kDa (hsc70) that selects peptide substrates, and multimeric lysosomal-associated membrane protein 2A (LAMP-2A) complex, facilitates the entry of peptide into the lysosome (Orenstein and Cuervo, 2010;Li et al, 2011b). MHCII antigen presentation of cytosolic glutamate decarboxylase in human B lymphoblastoid cells is reduced following knockdown of LAMP-2 or hsc70 (Zhou et al, 2005).…”

Section: Autophagy In Mhc Class II Antigen Presentationmentioning

confidence: 99%

Intersection of autophagy with pathways of antigen presentation

Patterson

Mintern

2012

Protein Cell

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Traditionally, macroautophagy (autophagy) is viewed as a pathway of cell survival. Autophagy ensures the elimination of damaged or unwanted cytosolic components and provides a source of cellular nutrients during periods of stress. Interestingly, autophagy can also directly intersect with, and impact, other major pathways of cellular function. Here, we will review the contribution of autophagy to pathways of antigen presentation. The autophagy machinery acts to modulate both MHCI and MHCII antigen presentation. As such autophagy is an important participant in pathways that elicit host cell immunity and the elimination of infectious pathogens.

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Chaperone-mediated autophagy: Molecular mechanisms and physiological relevance

Cited by 241 publications

References 52 publications

The pathways of mitophagy for quality control and clearance of mitochondria

The pathways of mitophagy for quality control and clearance of mitochondria

Chaperone-mediated autophagy: roles in disease and aging

Intersection of autophagy with pathways of antigen presentation

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